We have been studying mechanisms of lymphocyte hyporesponsiveness in cytomegalovirus (CMV) mononucleosis. Acute infection is associated with infection of monocytes which express suppressor activity, and with an inversion of the normal ratio of suppressor to helper T lymphocytes. Lymphocytes with a cytotoxic-suppressor phenotype are increased while those with helper-inducer phenotype are diminished. Herpes simplex virus (HSV) has been used to productively or latently infect a human T lymphoblastoid cell line (CEM). Phytohemagglutinin (PHA) can activate HSV from latently infected cultures. Concanavalin A (Con A), antibody, interferon, or acyclovir can reduce or eliminate infectious virus from productively infected cells, although viral DNA is retained in these cells. Epstein-Barr virus (EBV)-induced B lymphocyte transformation and outgrowth are under immunoregulatory control. The cells and mediators involved in this control are under investigation both in vitro and in vivo.